Proliferation, apoptosis, metastasis, and the like of tumors are closely related to the abnormal activity of protein kinases in a series of intracellular and extracellular signal transduction pathways. The abnormal activity of protein kinases not only directly associates with a tumor, but also leads to a series of human diseases associated with inflammation or proliferative responses, such as rheumatoid arthritis, cardiovascular diseases, nervous system diseases, asthma, psoriasis, and the like. At present, more than four hundred kinds of human diseases are known as being directly or indirectly associated with protein kinases, such that protein kinase has become an important medicine target.
Anaplastic lymphoma kinase (ALK), as a receptor tyrosine kinase, is a member of the insulin receptor superfamily and plays an important role in tumor cell growth and development. ALK gene can fuse with a variety of protein genes, be expressed to produce ALK protein, and can also generate variations such as mutation, amplification, and the like. In 1997, the oncogenic ALK gene rearrangement on the short arm of chromosome 2 of allobiosis large cell lymphoma was originally described, whereafter it was also found in other malignancies including diffuse large B-cell lymphoma and malignant tissues ball histiocytosis, as well as a variety of solid tumors including inflammatory myofibroblastic tumor, esophageal squamous cell carcinoma, neuroblastoma along with non-small cell lung carcinoma (NSCLC) recently reported.
In 2007, it was originally reported that ALK gene may encode and produce ALK by fusing with EML4 gene to form fusion gene, and thereby promote the growth of lung cancer cells. EML4-ALK fusion is caused by the insertion of the short arm of chromosome 2, and many types of variations have been found to date. Test shows that all of the fusion genes have biological functions, and the product they express is a chimeric tyrosine kinase, which began to be reported gradually in the study associated with NSCLC since 2007.
Because of the discovery of EML4-ALK fusion gene and the unique effect of the ALK inhibitor in the subgroup population thereof, NSCLC can be divided into different subtypes such as EGFR mutation, KRAS mutation, EML4-ALK gene fusion type, and the like, according to different molecular pathogenesis. In general NSCLC patients, the positive rate of EML4-ALK fusion gene is low in a range of between about 3% to 7%. EML4-ALK fusion gene mainly presents in non-smoking lung adenocarcinoma patients, and is mutually repulsive with both EGFR mutation and KRAS mutation. A study in 2010 showed that EML4-ALK fusion gene positive rate was 16.13% in Chinese lung adenocarcinoma patients, significantly higher than that of European and American patients; the positive rate was 19.23% in non-smoking lung adenocarcinoma patients; the mutation rate thereof was up to 42.8% in lung adenocarcinoma patients without EGFR and KRAS mutations.
Although a large amount of compounds with protein kinase inhibitory activity have been studied, and some protein kinase inhibitors have been launched for the antitumor therapy, drug resistance may arise. Therefore, it is urgent to develop new protein kinase inhibitors, such as ALK kinase inhibitors, for the prevention, mitigation and/or treatment of cancers mediated by protein kinases (such as ALK), such as ALK-positive non-small cell lung carcinoma (NSCLC) and the like.